It is generally accepted that anesthetics inhibit the functions of proteins indirectly via their effects upon the properties of the phospholipid domain. We believe that the properties of both lipids and proteins are both influenced by anesthetics. The present study is aimed at elucidating direct anesthetic-protein interactions. We have proposed that anesthetics change the conformation of lipid-protein complexes of cell membranes to relax their structure, and decrease the surface charge density, and make the membrane interface more hydrophobic. This will make the penetration of the membrane by hydrated cations more sluggish and the depolarization may be antagonized. Due to the decrease of surface charge density, the electrostricted water structure is destroyed and the volume of the total system expands, which is the chief cause of the well-known pressure reversal of anesthesia. Since the membrane proteins which constitute the excitation machinery are not accessible at present, model proteins are employed. Because the interfacial pH of proteins is different from the bulk pH mainly due to the ionic electrostatic fields, the surface charges are probed by pH-indicator dyes and pH-sensitive fluorophores. The change of the number of water molecules in the electrostricted hydration shell of the proteins by anesthetic is estimated by the measurement of the fluid density, combined with the measurements of the partial molal expansibility and compressibility. The binding of charged ligands containing hydrophobic parts, such as the dye molecules, involves ionic as well as hydrophobic interactions. Ionic and hydrogen bond formations are usually enthalpic process with negative delta H, while the force of hydrophobic interaction is mainly entropic. From the temperature coefficient of the binding of the chromophore, these thermodynamic parameters are obtained and are used to estimate the change of the interfacial hydrophobibity of the proteins by anesthetics.